It is known that many of small molecular weight anti-cancer agents have significant toxicity. Over the years, there have been various attempts to reduce the toxicity and improve the efficacy of small molecular weight anti-cancer agents.
One attempt to reduce the toxicity and improve the efficacy of small molecular weight drugs was directed to targeting agent-directed drug delivery systems. For example, the targeting agent such as single-chain antibody, RGD peptides, or folic acid, can direct the delivery of the therapeutic agent and improve its therapeutic effect. At the same time, the targeted delivery of very potent chemotherapeutics would reduce its toxicity. The approach has been validated by FDA's approval of, for example, Wyeth's Mylotarg® gemtuzumab zogamicin, a humanized antibody against CD33 linked to the calicheamicin cytotoxin, for acute myeloid leukemia (AML).
Traditionally, the immunoconjugates include three components: a targeting agent like a monoclonal antibody, a cytotoxin and a linker.
However, this approach requires that the antibody retain high degree of its binding affinity to its antigen after conjugation to the drug. Furthermore, the antibody-drug conjugates have to be stable in buffers or plasma and not prematurely release the toxin during circulation. They must also be internalized once the antibody binds its antigen on tumor cell surface. Thereafter, the drug molecule has to be released intact inside the targeted tumor cells at a desired speed.
Single chain antibodies (SCA's) or single-chain antigen-binding antibodies include the binding domain of full length antibody with only one fourth of the size. However, SCA can bind to antigen specifically with high affinity. A description of the theory and production of single-chain antigen-binding proteins is found, for example, in commonly-assigned U.S. Pat. Nos. 4,946,778, 5,260,203, 5,455,030 and 5,518,889. The single-chain antigen-binding proteins produced under the process recited in the above U.S. patents have binding specificity and affinity substantially similar to that of the corresponding Fab fragment, the content of which are incorporated by reference herein. More recently, commonly-assigned U.S. Pat. No. 6,872,393 disclosed polyalkylene oxide-modified single chain polypeptides. The contents of each of the foregoing commonly-assigned patents are incorporated herein by reference.
In spite of the attempts and advances, there continues to be a need to provide targeting agent-directed polymeric drug delivery system having desired therapeutic activity and less toxicity. The present invention addresses this need and others.